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Protective effects of Tongxinluo on cerebral ischemia/reperfusion injury related to Connexin 43/Calpain II/Bax/Caspase-3 pathway in rat.
J Ethnopharmacol. 2017 Feb 23; 198:148-157.JE

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE

Tongxinluo (TXL) is a multifunctional traditional Chinese medicine and has been widely used in the treatment of cardiovascular and cerebrovascular diseases. Numerous studies demonstrate that TXL is a novel neuroprotective drug, however, the mechanisms are largely unknown.

AIM OF THE STUDY

we aimed to demonstrate the protective effect of TXL on cerebral ischemia/reperfusion (I/R) injury and provide the evidence for the involvement of Connexin 43/Calpain II/ Bax/Caspase-3 pathway in TXL-mediated neuroprotection.

METHODS

Focal cerebral I/R injury were induced by transient middle cerebral artery occlusion (MCAO, for 90min) in adult male Sprague-Dawley rats. We estimated the effects of TXL on I/R injury including neurological deficit assessment and cerebral infarct volume measurement via TTC staining, and detected the protein expression of Connexin 43 (Cx43) by western blot. Furthermore, after the intracerebroventricular injection of carbenoxolone (CBX, the inhibitor of Cx43) at 30min before MCAO surgery, Calpain II, Bax and cleaved Caspased-3 immunoreactivity in ischemic penumbra region was detected by immunofluorescent staining, and cell apoptosis was detected by TUNEL staining.

RESULTS

TXL treatment greatly improved neurological deficit and reduced the infarction volume compared to MCAO with buffer treatment (P<0.05), and TXL pre-post treatment showed better results than TXL pre-treatment. TXL pre-post treatment significantly up-regulated Cx43 protein expression at 3d, 7d and 14d post-injury compared to MCAO with buffer treatment (P<0.05). Meanwhile, the immunoreactivity of Calpain II, Bax and cleaved Caspase-3 in ischemic penumbra region was obviously decreased by TXL pre-post treatment compared to MCAO group (P<0.05). However, with the treatment of the Cx43 inhibitor, CBX, the down-regulated effect of TXL on Calpain II, Bax and cleaved Caspase-3 immunoreactivity was abolished (P<0.05). Moreover, the protective effect of TXL against neuron apoptosis in penumbra region was conteracted by CBX (P<0.05).

CONCLUSIONS

TXL could effectively protect against I/R injury and reduced cell death via Cx43/Calpain II/Bax/Caspase-3 pathway, which contribute to I/R injury prevention and therapy.

Authors+Show Affiliations

Department of Neurology, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510120, China; The Second Institute of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510120, China. Electronic address: chengxiaolucky@126.com.Department of Neurology, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510120, China; The Second Institute of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510120, China; Medical Experimental Center, Nanyang Institute of Technology, Nanyang 473004, P.R. China. Electronic address: jiyun0728@163.com.Department of Neurology, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510120, China; The Second Institute of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510120, China. Electronic address: 1534873641@qq.com.Department of Neurology, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510120, China; The Second Institute of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510120, China. Electronic address: 1440124821@qq.com.Department of Neurology, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510120, China; The Second Institute of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510120, China. Electronic address: 747635117@qq.com.Department of Neurology, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510120, China; The Second Institute of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510120, China. Electronic address: 278137393@qq.com.Department of Anatomy, Zhong Shan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China. Electronic address: 554776504@qq.com.Department of Neurology, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510120, China; The Second Institute of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510120, China. Electronic address: hzdxliyan0719@163.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28065778

Citation

Cheng, Xiao, et al. "Protective Effects of Tongxinluo On Cerebral Ischemia/reperfusion Injury Related to Connexin 43/Calpain II/Bax/Caspase-3 Pathway in Rat." Journal of Ethnopharmacology, vol. 198, 2017, pp. 148-157.
Cheng X, Hou Z, Sun J, et al. Protective effects of Tongxinluo on cerebral ischemia/reperfusion injury related to Connexin 43/Calpain II/Bax/Caspase-3 pathway in rat. J Ethnopharmacol. 2017;198:148-157.
Cheng, X., Hou, Z., Sun, J., Huang, Y., Wang, L., Zhou, Z., Zhou, L. H., & Cai, Y. (2017). Protective effects of Tongxinluo on cerebral ischemia/reperfusion injury related to Connexin 43/Calpain II/Bax/Caspase-3 pathway in rat. Journal of Ethnopharmacology, 198, 148-157. https://doi.org/10.1016/j.jep.2017.01.004
Cheng X, et al. Protective Effects of Tongxinluo On Cerebral Ischemia/reperfusion Injury Related to Connexin 43/Calpain II/Bax/Caspase-3 Pathway in Rat. J Ethnopharmacol. 2017 Feb 23;198:148-157. PubMed PMID: 28065778.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protective effects of Tongxinluo on cerebral ischemia/reperfusion injury related to Connexin 43/Calpain II/Bax/Caspase-3 pathway in rat. AU - Cheng,Xiao, AU - Hou,Zijun, AU - Sun,Jingbo, AU - Huang,Yan, AU - Wang,Lixin, AU - Zhou,Ziyi, AU - Zhou,Li-Hua, AU - Cai,Yefeng, Y1 - 2017/01/05/ PY - 2016/02/01/received PY - 2016/12/22/revised PY - 2017/01/04/accepted PY - 2017/1/10/pubmed PY - 2017/7/27/medline PY - 2017/1/10/entrez KW - Cell apoptosis KW - Cerebral ischemia/reperfusion injury KW - Connexin43 KW - Ischemic penumbra region KW - Tongxinluo capsule SP - 148 EP - 157 JF - Journal of ethnopharmacology JO - J Ethnopharmacol VL - 198 N2 - ETHNOPHARMACOLOGICAL RELEVANCE: Tongxinluo (TXL) is a multifunctional traditional Chinese medicine and has been widely used in the treatment of cardiovascular and cerebrovascular diseases. Numerous studies demonstrate that TXL is a novel neuroprotective drug, however, the mechanisms are largely unknown. AIM OF THE STUDY: we aimed to demonstrate the protective effect of TXL on cerebral ischemia/reperfusion (I/R) injury and provide the evidence for the involvement of Connexin 43/Calpain II/ Bax/Caspase-3 pathway in TXL-mediated neuroprotection. METHODS: Focal cerebral I/R injury were induced by transient middle cerebral artery occlusion (MCAO, for 90min) in adult male Sprague-Dawley rats. We estimated the effects of TXL on I/R injury including neurological deficit assessment and cerebral infarct volume measurement via TTC staining, and detected the protein expression of Connexin 43 (Cx43) by western blot. Furthermore, after the intracerebroventricular injection of carbenoxolone (CBX, the inhibitor of Cx43) at 30min before MCAO surgery, Calpain II, Bax and cleaved Caspased-3 immunoreactivity in ischemic penumbra region was detected by immunofluorescent staining, and cell apoptosis was detected by TUNEL staining. RESULTS: TXL treatment greatly improved neurological deficit and reduced the infarction volume compared to MCAO with buffer treatment (P<0.05), and TXL pre-post treatment showed better results than TXL pre-treatment. TXL pre-post treatment significantly up-regulated Cx43 protein expression at 3d, 7d and 14d post-injury compared to MCAO with buffer treatment (P<0.05). Meanwhile, the immunoreactivity of Calpain II, Bax and cleaved Caspase-3 in ischemic penumbra region was obviously decreased by TXL pre-post treatment compared to MCAO group (P<0.05). However, with the treatment of the Cx43 inhibitor, CBX, the down-regulated effect of TXL on Calpain II, Bax and cleaved Caspase-3 immunoreactivity was abolished (P<0.05). Moreover, the protective effect of TXL against neuron apoptosis in penumbra region was conteracted by CBX (P<0.05). CONCLUSIONS: TXL could effectively protect against I/R injury and reduced cell death via Cx43/Calpain II/Bax/Caspase-3 pathway, which contribute to I/R injury prevention and therapy. SN - 1872-7573 UR - https://www.unboundmedicine.com/medline/citation/28065778/Protective_effects_of_Tongxinluo_on_cerebral_ischemia/reperfusion_injury_related_to_Connexin_43/Calpain_II/Bax/Caspase_3_pathway_in_rat_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-8741(17)30052-1 DB - PRIME DP - Unbound Medicine ER -